Mechanism of allosteric effects of ATP on the kinetics of P-type ATPases.

The roles of allosteric effects of ATP and protein oligomerisation in the mechanisms of P-type ATPases belong to the most controversial and least well understood topics in the field. Recent crystal structural and kinetic data, however, now allow certain hypotheses to be definitely excluded and consistent hypotheses to be developed. The aim of this review is to critically discuss recent results and, in the light of them, to present a set of conclusions which could form the basis of future research. The major conclusions are: (1) at saturating ATP concentrations P-type ATPases function as monomeric enzymes, (2) the catalytic units of P-type ATPases only possess a single ATP binding site, (3) at non-saturating ATP concentrations P-type ATPases exist as diprotomeric (or higher oligomeric) complexes, (4) protein-protein interactions within a diprotomeric complex enhances the enzymes' ATP binding affinity, (5) ATP binding to both protomers within a diprotomeric complex causes it to dissociate into two separate monomers. The physiological role of protein-protein interactions within a diprotomer may be to enhance ATP binding affinity so as to scavenge ATP and maximize the ion pumping rate under hypoxic or anoxic conditions. For the first time a structural basis for the well-known ATP allosteric acceleration of the E2 --> E1 transition is presented. This is considered to be due to a minimization of steric hindrance between neighbouring protomers because of the ability of ATP to induce a compact conformation of the enzymes' cytoplasmic domains.